Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists

Abstract

This invention provides a compound of the formula (I): wherein, variables A, B, D, E, and R 1 to R 11 are as defined in the specification.

1. A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein A and B are independently CR 12  or N; D and E are each independently CR 9  or N; R 1  represents (C 1 -C 6 )alkyl; R 2  represents hydrogen, halogen, hydroxy, (C 1 -C 6 ) alkyl, halo(C 1 -C 6 ) alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; R 3 , R 4 , R 5 , R 6 , R 10  and R 11  each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; or R 3  and R 4  are taken together with the carbon atom to which they are attached to form a 3- to 7-membered carbocyclic ring or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom, a sulfur atom or NH; R 7  and R 9  each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, NH 2 , [(C 1 -C 6 )alkyl]NH—, [(C 1 -C 6 )alkyl] 2 N—, H 2 N—(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkoxy, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy; H 2 N—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl or 5- or 6-membered heterocyclic ring containing at least one nitrogen atom; R 8  represents halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylsulfonyl, halo(C 1 -C 6 )alkylsulfinyl, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkylthio, [(C 1 -C 6 )alkyl]NH— or [(C 1 -C 6 )alkyl] 2 N—; or R 7  and R 8 , when E is CR 9 , are taken together with the carbon atoms to which they are attached form a 5-8 membered carbocyclic or heterocyclic ring, in which one or two non-adjacent carbon atoms are optionally replaced by oxygen, sulfur, N or NH groups, wherein the carbocyclic ring or the heterocyclic ring is unsubstituted or substituted with one or more substituents each independently selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and hydroxy(C 1 -C 6 )alkyl; and R 12  represents hydrogen, halogen, (C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; 
       with the proviso that one and only one A, B, D, or E is N; 
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound according to  claim 1 , wherein A represents CR 12  and D represents CR 9 ; R 1  represents (C 1 -C 3 )alkyl; R 3  and R 4  each independently represents hydrogen or (C 1 -C 3 )alkyl; R 5  represents hydrogen, R 7  represents hydrogen, halogen, hydroxy(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N—, pyridyl, piperidino, pyrrolidino or morpholino; R 8  represents (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkylthio or halo(C 1 -C 3 )alkylsulfonyl; and R 12  represents hydrogen, halogen, (C 1 -C 3 )alkyl or hydroxymethyl. 
     
     
       3. A compound according to  claim 1 , wherein R 10  and R 11  each independently represents hydrogen. 
     
     
       4. A compound according to  claim 1 , wherein R 1  represents methyl; R 3  and R 4  each independently represents hydrogen, methyl or ethyl; and R 8  represents tert-butyl, trifluoromethyl, 2,2,2-trifluoro-1,1-dimethylethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, 2-hydroxy-1,1-dimethylethyl or 2-methoxy-1,1-dimethylethyl. 
     
     
       5. A compound according to  claim 1 , wherein R 2  represents hydrogen, fluoro, methyl, ethyl, hydroxymethyl or hydroxyethyl; R 4  and R 5  each independently represents hydrogen; R 6  represents hydrogen, methyl, ethyl, methoxy or hydroxymethyl; R 7  and R 9  each independently represents hydrogen or fluoro; and R 12  represents hydrogen, fluoro, methyl, ethyl, hydroxymethyl or hydroxyethyl. 
     
     
       6. A compound according to  claim 1 , wherein R 3  represents methyl or ethyl; and R 8  represents tert-butyl, trifluoromethyl, 2,2,2-trifluoro-1,1-dimethylethyl, trifluoromethoxy or trifluoromethylthio. 
     
     
       7. A compound according to  claim 1 , wherein R 6  represents methyl, ethyl or methoxy. 
     
     
       8. A compound according to  claim 1 , wherein R 5  and R 6  are trans. 
     
     
       9. A compound according to  claim 1  selected from;
 2-Methyl-N-((1R)-1-{6-methyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)-2-[4-(2,2,2-trifluoro-1, 1-dimethylethyl)phenyl]cyclopropanecarboxamide; 
 2-(6-tert-Butylpyridin-3-yl)-2-methyl-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-Methyl-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]cyclopropanecarboxamide; 
 (1S,2S)-2-Methyl-N-((1R)-1-{6-methyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)-2-[4-(trifluoromethyl)phenyl]cyclopropanecarboxamide; 
 N-((1R)-1-{6-Ethyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)-2-methyl-2-[4-(2,2,2-trifluoro-1,1-dimethylethyl)phenyl]cyclopropanecarboxamide; 
 2-Methyl-N-((1R)-1-{4-methyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)-2-[4-(2,2,2-trifluoro-1, 1-dimethylethyl)phenyl]cyclopropanecarboxamide; 
 N-((1R)-1-{3-Methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)-2-[2-pyrrolidin-1-yl-6-(trifluoromethyl) pyridin-3-yl]cyclopropanecarboxamide; 
 N-((1R)-1-{3-(Hydroxymethyl)-4-[(methylsulfonyl)amino]phenyl}ethyl)-2-[2-pyrrolidin-1-yl-6-(trifluoromethyl) pyridin-3-yl]cyclopropanecarboxamide; 
 2-(6-tert-Butyl-2-piperidin-1-ylpyridin-3-yl)-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-(6-tert-Butyl-2-piperidin-1-ylpyridin-3-yl)-N-((1R)-1-{3-fluoro-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-(6-tert-Butyl-2-pyrrolidin-1-ylpyridin-3-yl)-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-[6-tert-Butylpyridin-3-yl]-N-((1R)-1-{3-fluoro-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-[6-tert-Butylpyridin-3-yl]-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 (1S,2S)-2-Methyl-N-((1R)-1-{6-methyl-5-[(methylsulfonyl)amino[pyridin-2-yl}ethyl)-2-(4-trifluoromethyl)phenyl]cyclopropanecarboxamide; 
 2-[4-tert-Butylphenyl]-N-((1R)-1-{6-methyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)cyclopropanecarboxamide; 
 N-((1R)-1-{6-Methyl-5-[(methylsulfonyl)amino]pyridin-2-yl}ethyl)-2-[4-(trifluoromethyl)phenyl]cyclopropanecarboxamide; 
 2-[6-tert-Butylpyridin-3-yl]-2-ethyl-N-((1R)-1-{3-methyl-4-[(sulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; 
 2-[2-(Dimethylamino)-6-(trifluoromethyl)pyridin-3-yl]-N-((1R)-1-{2-fluoro-5-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)cyclopropanecarboxamide; and 
 2-Methyl-N-((1R)-1-{3-methyl-4-[(methylsulfonyl)amino]phenyl}ethyl)-2-[2-morpholin-4-yl-6-(trifluoromethyl)pyridin-3-yl]cyclopropanecarboxamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       10. A pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in  claim 1 , together with a pharmaceutically acceptable excipient.